This invention relates to media milling and in particular to media milling using two size distributions of milling media to obtain small particles of a solid material wherein the media are retained in the milling chamber of the media mill and the small particles are separated from the milling media.
Size reduction of crystalline and amorphous solids by mechanical means using dry or wet milling techniques such as jet milling, ball milling, media milling, or homogenization is now widely used in a variety of industries. Diverse industrial applications include the production of paints; pigments; photographic materials; cosmetics; chemicals; metal powders useful as catalysts and supports; stationary phase particles useful in analytical and preparative chromatographic separations of chemical compounds and mixtures such as those encountered in forensic science, food, cosmetics, chemical, and pharmaceutical studies; powdered toners, both black and colored, useful in xerographic and printing applications including laser printing; and small particles of solid pharmaceutical agents including water-soluble, water-insoluble, and poorly water-soluble therapeutic and diagnostic imaging agents, medicinally active agents, medicaments, plant and herbal extracts, drugs, pro-drugs, drug formulations, diagnostic imaging agents, and the like. In pharmaceutical applications it is often desirable to prepare very small particles of an essentially water-insoluble or poorly water solid because the rate of dissolution of a particle and often the bioavailability of an essentially water-insoluble or poorly water-soluble drug can increase with increasing surface area, i.e., decreasing particle size.
Examples of mills used to accomplish particle size reduction include colloid mills, swinging mills, ball mills, media mills, attritor mills, jet mills, vibratory mills, and high pressure homogenizers. Size reduction methods are described, e.g., in U.S. Pat. Nos. 4,006,025, 4,294,916, 4,294,917, 4,940,654, 4,950,586 and 4,927,744, and UK 1,570,362.
In a communition or milling process, repeated collisions of milling media with a solid material being milled, i.e., the milled substrate, result in repeated fracture of the substrate and concomitant substrate particle size reduction. When a media milling process is used to reduce the size of particles of a substrate, the process is usually carried out in a mill comprising a milling chamber containing milling media, a solid material or substrate which is to be milled, and a liquid or gaseous fluid carrier in which the media and substrate are suspended. The contents of the milling chamber are stirred or agitated with an agitator which transfers energy to the milling media. The accelerated media collide with the substrate in energetic collisions that can crush, chip, fracture or otherwise reduce the size of the solid substrate material and lead to an overall reduction in substrate particle size and an overall reduction in substrate average or mean particle size distribution.
Milling media are generally selected from a variety of dense and hard materials, such as sand, steel, silicon carbide, ceramics, zirconium silicate, zirconium and yttrium oxide, glass, alumina, titanium, and certain polymers such as crosslinked polystyrene and methyl methacrylate. Polymeric media are sometimes preferable to conventional inorganic media because they do not degrade to deposit metal oxides and soluble salts in the milled substrate and pH fluctuations and chemical changes can be minimized during milling. Such changes may impair dispersion stability, hydrolyze certain solids, and alter milling performance. Media geometries may vary depending on the application, although spherical or cylindrical beads are most commonly used.
Milling media can be of various sizes and size distributions that include large milling media particles and smaller milling media particles. The size distribution of the milling media can be narrow in which case the media are substantially uniform or nearly uniform in size. Alternatively, more than one narrow size distribution of media can be used. If two substantially different media sizes are used wherein substantially all of the media can be classified as being of either one or the other size, then the size distribution of the milling media can be described as being bimodal. Bimodal size distributions of milling media are often used in a milling chamber containing a separator having openings smaller than the smallest size of media used. Such a separator or screen will not allow any size of media used in a bimodal or broad distribution of media sizes to pass out of the milling chamber. Alternatively, the milling media can be sufficiently small that substantially all of the milling media can pass through the openings in the separator or screen and thus pass out of the milling chamber. Alternatively, the size of the openings in the milling separator can be small enough to prohibit passage of one size distribution of media (i.e., a larger size) but permit the passage of another size distribution of media (i.e., a smaller size distribution of milling media).
Mills useful for reducing the particle size of a solid substrate can operate in a batchwise mode or in a continuous or semi-continuous mode. Mills operating in a continuous mode often incorporate a means such as a separator or screen for retaining milling media together with relatively large particles of the solid substrate being milled in the milling zone or milling chamber of the mill while allowing smaller particles of the substrate being milled, i.e., product substrate particles, to pass out of the milling chamber in either a recirculation or discrete pass mode. Recirculation is often in the form of a dispersion such as a slurry, suspension, dispersion, or colloid of the substrate suspended in a fluid carrier phase that moves from the milling chamber into an often stirred holding vessel and thence back to the milling chamber, frequently with the aid of a pump. A separator or screen is effectively located at the outlet port of the milling chamber. Such means for simultaneous milling and media separation are referred to as xe2x80x9cdynamic media separationxe2x80x9d.
In another method of continuous milling of a substrate, mills operating in a continuous mode can incorporate a means for retaining relatively large particles of the solid substrate being milled in the milling zone or milling chamber of the mill while allowing smaller particles of the substrate being milled, i.e., product substrate particles, as well as the milling media to pass out of the milling chamber in either a recirculation or discrete pass mode. In recirculation mode, the product substrate particles and the media suspended in a fluid carrier move from the milling chamber through the separator or screen into an often stirred holding vessel and thence back to the milling chamber, frequently with the aid of a pump.
In yet another method of continuous milling of a substrate, mills operating in a continuous mode can incorporate a means for retaining both relatively large particles of the solid substrate being milled and large size milling media in the milling chamber of the mill while allowing smaller particles of the substrate being milled, i.e., product substrate particles, as well as small size milling media to pass out of the milling chamber in either a recirculation or discrete pass mode. In recirculation mode, the product substrate particles and the small size media suspended in a fluid carrier move from the milling chamber through a separator or screen into an often stirred holding vessel and thence back to the milling chamber, frequently with the aid of a pump.
In a batch process, the milling media, the fluid carrier, and the substrate being milled remain in the vessel until the fractured substrate particles have been reduced to the desired size or to a minimum size achievable. The fluid carrier and the product substrate particles are then separated from the media particles with a separator or screen at the outlet port of the milling chamber.
Various techniques have been established for retaining media in media mills, including media separators such as rotating gap separators, screens, sieves, centrifugally-assisted screens, and similar devices to physically restrict passage of media from the mill. Retention of media arises because the dimensions of the milling media are larger than the dimensions of the openings through which the reduced size substrate particles can pass.
In batch processes employing ball mills (e.g. Abbe Ball Mills) or stirred ball mills (e.g. Union Process Attritor) separation of dispersion and milling media is performed after milling is complete, usually through a screen or sieve or filter sized smaller than the milling media. Typically, the screen is affixed to the milling vessel and slurry is removed by gravity drainage or pumped out of the vessel to pass through the filter. Alternatively, the slurry may be forced from the vessel by charging the vessel with compressed gas. However, the use of relatively large size milling media can impose a practical limitation to the final size of the substrate particles produced in the milling process.
In recent years there has been a transition to the use of small milling media in conventional media mill processes of solid substrates for the preparation of various paints, pigment dispersions, photographic, pharmaceutical dispersions, and the like. The advantages obtained with the use of smaller size media include faster rates of substrate particle size reduction and more rapid attainment of smaller substrate particle size distributions as products of the milling process, i.e., more efficient comminution. Improvements in conventional media mill designs such as in Netzsch LMC mills and Drais DCP mills have incorporated smaller screen opening dimensions that allow physical separation of larger milling media from substrate particles as small as 250 to 300 micrometers or less. However, even with the best machine designs available, it is generally not possible to use media smaller than about 250 to 300 micrometers due to separator screen plugging proximal to the milling chamber and unacceptable pressure build-up due to hydraulic packing of the media. Commonly, for commercial applications, a grinding media size of 350 micrometers is considered the practical lower limit for media particle retention due to media separator screen limitations.
The use of media that are smaller than the screen opening size in conventional media mills has permitted the reduction of solid substrates to particle sizes on the order of about 50 micrometers. For example, Czekai et al. in U.S. Pat. Nos. 5,513,803 and 5,718,388 disclose the use of ultrafine milling media for the preparation of fine particles useful in imaging elements and pigments. However, the mill media separator gaps were selected to be at least two to ten times the size of the smaller media such that both the smaller media and the reduced size substrate product particles could pass through the separator gaps in the mill. This resulted in a need for continuous addition of a mixture of smaller media and substrate to the milling chamber and continuous removal of a mixture of smaller media and reduced size substrate product from the milling chamber. In addition, removal of the substrate product from the smaller size milling media required a later separation step. Simultaneous use of a mixture of large and small size milling media wherein the larger size media were retained in the milling chamber and a smaller size media were not retained within the milling chamber still required a later step after milling to separate the smaller media from the milled substrate product.
Liversidge et al. in U.S. Pat. No. 5,145,684 and in European Patent Application 498,492 describe dispersible particles consisting of a drug substance or an x-ray contrast agent having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. The particles are prepared by dispersing a drug substance or imaging agent in a liquid dispersion medium and wet grinding in the presence of rigid grinding media. Liversidge et al. do not suggest a continuous milling process using at least two size distributions of milling media wherein one size distribution is smaller that the openings in a media separator device in the milling chamber of a media mill and wherein the grinding media is separated from the pharmaceutical agent inside the milling chamber and the grinding media is retained in the milling chamber.
Bruno et al. in U.S. patent application Ser. No. 07/981,639 filed Nov. 25, 1992 entitled Method for Grinding Pharmaceutical Substances disclose polymeric grinding media for fine grinding pharmaceutical compositions.
U.S. Pat. No. 5,662,279 describes the milling of a slurry of a compound using rigid milling media to reduce the particle size of the compound. However, removal of the product from the milling media was done in a subsequent step by vacuum filtration through a removable filter probe attached to a conduit immersed in the slurry.
U.S. Pat. Nos. 5,470,583 and 5,336,507 disclose methods for preparation of nanoparticles using a charged phospholipid as a cloud point modifier.
U.S. Pat. No. 5,302,401 discloses compositions and methods for forming nanoparticles with a surface modifier and a cryoprotectant adsorbed thereon.
U.S. Pat. No. 5,478,705 discloses a process for the preparation of solid particles of a compound useful in photographic, electrophotographic, or thermal transfer imaging elements having an average particle size of less than 1 micron which comprises milling the compound in the presence of milling media comprising a polymeric resin.
U.S. Pat. No. 5,500,331 discloses a method of preparing submicron particles of a material, such as a pigment useful in paints or a compound useful in imaging elements, which comprises milling the agent in the presence of milling media having a mean particle size of less than about 100 microns. In a preferred embodiment, the milling media is a polymeric resin.
U.S. Pat. No. 5,518,187 discloses a method of preparing particles of a drug substance or diagnostic imaging agent that comprises grinding the drug substance or imaging agent in the presence of grinding media comprising a polymeric resin. It further discloses a method of preparing particles of a drug substance or a diagnostic imaging agent by grinding with rigid grinding media to reduce said particles to submicron size, wherein said grinding media has a substantially spherical shape, has a particle size range of 0.1 to 3 mm and comprises a polymeric resin.
U.S. Pat. No. 5,534,270 discloses a method of preparing sterilized nanoparticulate crystalline drug particles comprising the steps of providing a drug substance having a solubility in water of less than 10 mg/ml; depyrogenating rigid grinding media having an average particle size less than 3 mm; mixing and autoclaving the drug substance and rigid grinding media; and adding a surface modifier to the autoclaved drug substance and rigid grinding media to a dispersion medium such as water and wet grinding the drug substance sufficiently to maintain an effective average particle size of less than 400 nm. The rigid grinding media is selected from the group consisting of zirconium silicate beads, zirconium oxide stabilized with magnesia and glass beads.
U.S. Pat. No. 5,657,931 discloses a process for the preparation of a fine solid particle aqueous dispersion of a substantially water-insoluble non-polymeric organic compound useful in imaging which process comprises forming a coarse aqueous slurry of solid particles of said compound and an amphipathic water-soluble or water-dispersible block polymeric dispersant having an HLB number of at least 8 and then milling said slurry for a period of time sufficient to provide particles of the desired particle size of less than 0.5 micron.
U.S. Pat. No. 5,704,556 discloses a process for rapidly producing colloidal particles, the process comprising providing a feedstock slurry having an average particle size less than one micron to a stirred media mill, the slurry including from about 5 to 10 percent by weight dispersant; and a total solids of less than about 50 percent by weight in a low viscosity fluid; providing ceramic beads selected from zircon, glass and yttrium toughened zirconium oxide less than 100 microns in diameter in the mill; filling the mill to a volume in excess of 90%; operating the mill at tip speeds at least 20 meters/sec; and limiting the residence time to less than about two minutes, thereby producing particles having an average particle size less than about 0.1 micron from the feedstock. In one aspect, the diameter of the ceramic beads is no more than about one hundred times the average particle size of the feedstock particles.
U.S. Pat. No. 5,862,999 discloses a method of grinding particles of a therapeutic or diagnostic agent in which the agent is ground in the presence of rigid grinding media having a mean particle size of less than about 100 microns. The therapeutic or diagnostic agent particles produced by the grinding process have an average particle size of less than about 500 nm.
U.S. Pat. No. 5,902,711 discloses a process of forming milled solid particles of an electrophotographic toner pigment compound comprising milling solid particles of the compound in a liquid organic medium continuous phase in the presence of polymeric milling media to reduce the average size of the compound particles. The liquid continuous phase such as an ethylenically unsaturated polymerizable monomer comprises a solvent for the milling media polymer in the uncrosslinked form and the milling media is crosslinked sufficiently to prevent 50 volume per cent swelling of the polymeric milling media in the liquid continuous phase within four hours at 25xc2x0 C. The polymeric milling media can have a mean particle size of less than about 100 micrometers in the unswelled state prior to addition to the liquid organic continuous phase. The compound particles are milled to an average particle size of less than 100 nm. The milling media polymer comprises polymerized styrene and divinylbenzene monomers.
International Patent Application WO 99/39700 describes the preparation of submicron nanoparticles from a pharmacologically active principle and a composite material consisting of at least one lipidic substance and at least one amphiphilic substance using high pressure homogenization to form a microemulsion of the composite material at a temperature higher than the melting temperature of at least one of the materials forming the composite and in the presence of one or more aqueous surfactants as surface active substances and then cooling the microemulsion to form a dispersion of solid particles.
U.S. Pat. No. 5,922,355 discloses a method for preparing submicron size microparticles by particle size reduction methods in which a solid material is reduced in size over a period of time while continuously below the melting point of the material or by precipitation while the particles are stabilized with phospholipids as surface active substances in combination with other surface modifiers to control growth of particle size and enhance storage stability. The use of one or more surface modifiers in addition to a phospholipid provides volume weighted mean particle size values that are much smaller than what can be achieved using phospholipid alone without the use of an additional surface active substance (surfactant) with the same energy input while providing compositions resistant to particle size growth on storage. The phospholipid and the surfactant are both present at the time of particle size reduction.
U.S. Pat. No. 5,700,471 discloses a process for the micronization of compounds having low solubility in water by exposing such compounds briefly to a temperature above their respective melting points, dispersing them with turbulence in an aqueous or organic phase, and subsequently cooling the phase to form a fine particle dispersion.
U.S. Pat. No. 4,880,634 describes a method of production of an excipient system containing a pharmacologically active substance for peroral administration comprised of lipid nano-pellets in an aqueous, colloidal suspension. The method comprises forming a melt of a mixture of at least one surfactant, a pharmacologically active substance, and at least one lipid, dispersing the molten mixture within an aqueous solution at a temperature above the melting point of the lipid to form lipid nano-pellets, and cooling the suspension below the melting point of the lipid. In the process, a pharmacologically effective substance is thoroughly dissolved in the lipid or mixture of lipids during the preparation of the lipid nano-pellets.
U.S. Pat. Nos. 5,091,187 and 5,091,188 discloses water-insoluble drugs rendered injectable as aqueous dispersions of phospholipid-coated microcrystals. The crystalline drug is reduced to 50 nm to 10 micrometers by sonication or other processes inducing high shear in the presence of phospholipid or other membrane-forming amphipathic lipid.
WO 97/14407 discloses particles of water-insoluble biologically active compounds including drugs with an average size of 100 nm to 300 nm that are prepared by dissolving the compound in a solution and then spraying the solution into compressed gas, liquid, or supercritical fluid in the presence of appropriate surface modifiers.
The advantages in drug delivery of water-insoluble drugs formulated as small particles have been described in a review by Pace et al., xe2x80x9cNovel injectable formulations of insoluble drugs,xe2x80x9d in Pharmaceutical Technology, March 1999 the contents of which are hereby incorporated by reference.
It would be desirable to provide an improved milling and media separation process, particularly for use with media smaller than 350 micrometers, wherein the milling media are retained in the milling chamber and milled substrate particles in a carrier fluid are separated from the media.
It is an object of the invention to provide a milling process capable of making ultra-fine particle dispersions with weight average particle sizes less than 100 micrometers.
It is a further object to provide a milling process which enables the use of milling media less than 100 micrometers in weight average size whereby such media is separated from ultra-fine particle dispersions without plugging of a media separator.
It is a further object to provide a milling process in which milling media is not removed from the milling vessel to accomplish media/dispersion separation.
We have discovered a milling process for milling a solid substrate in the milling chamber of a media mill in the presence of a media separator of screen having openings of size S0 wherein the above objectives are achieved. In this invention, the milling media comprise a mixture of large size media and small size media. The large size media have a size S1 all of which are larger than S0; they will not pass through the separator and thus will remain in the milling chamber. The small size media have a size S2 that is at least smaller than S1 and is preferably smaller than S0. In this invention, large size media optionally in the presence of a fluid carrier are added to the milling chamber. The large size media form a depth filter comprising an array of contacted milling media and voids, channels, and spaces among the milling media particles distributed, stacked or layered on the exit screen of the milling chamber. The small size media are larger than the voids, channels, and spaces of the depth filter and thus will not pass through the depth filter even though they are smaller than the openings in the separator. Subsequently, a conglomerate comprising a solid to be milled, fluid carrier, small size media and optionally additional large size media are added to the milling chamber either directly or by being pumped from a reservoir or holding tank that is optionally stirred, and the solid is milled to produce very small particles of solid substrate. The very small particles are smaller than the smallest media size present in the milling chamber. During the milling process, at least a portion of the depth filter proximal to the exit screen is not agitated. The large media particles and the small media particles will not pass through the depth filter and remain in the milling chamber during and after the milling process. The fluid carrier and the very small particles of milled product substrate which are small enough to pass through the spaces, voids, and channels in the depth filter can pass out of the milling chamber and be separated from the milling media. The very fine particles are obtained free of milling media as a dispersion in the fluid carrier.
In another embodiment of the milling process of this invention, large size media of size S1 larger than S0 or a distribution of large size media having an average size S1 in which all are larger than S0 is added to the milling chamber of a media mill. The large size media are allowed to form a depth filter at an exit screen in the milling chamber of the media mill. The depth filter comprises one to several layers of large size media on the exit screen having openings of size S0. An agglomerate comprising a solid substrate to be milled and small size milling media of size S2 smaller than S0 or a distribution of small size media having an average size S2 smaller than S0 or a mixture of said small size media and additional large size media is added to the milling chamber. The solid substrate is mechanically milled by the media to produce very small particles of substrate product. The very small milled product substrate particles are continuously removed from the milling chamber as a dispersion in the fluid carrier and are separated from both the small and the large media by passage through the depth filter together with the fluid carrier. During the milling process, at least one layer of large media of the depth filter remains substantially non-agitated or undisturbed by the movement of any other milling media or substrate particles or fluid carrier in the milling chamber. Neither the large size milling media nor the small size milling media are removed from the milling chamber by passing through the openings in the separator. Fluid carrier that passed through the depth filter can be replaced with additional fluid carrier or be recirculated back into the media mill optionally in the form of a fluid carrier dispersion of very small milled substrate particles.
In accordance with one embodiment of the invention, we have discovered a process for preparing a dispersion of solid particles of a milled substrate in a fluid carrier comprising the steps of:
(a) providing a plurality of large size milling media to the milling chamber of a media mill and forming a depth filter therefrom on an exit screen or separator in the milling chamber;
(b) adding to said milling chamber a plurality of small size milling media optionally containing additional large size milling media, a conglomerate of a solid substance comprising a substrate to be milled and optionally one or more than one surface active substance, and a fluid carrier;
(c) milling said conglomerate in said milling chamber to produce very small milled substrate product particles; and
(d) separating said milled substrate particles suspended in said fluid carrier from the media through said depth filter; wherein:
the exit screen comprises openings of size S0;
the large size media have a size distribution S1 of which all are larger than S0;
the small size media have a size distribution S2 which are smaller than S0;
the very small milled substrate particles have a size distribution S3 and are smaller than all of the small media; and
the large size media and the small size media are retained in the milling chamber.
In another aspect of this invention, the milling media comprise a mixture of large size media and small size media. The large size media have a size S1 all of which are larger than S0; they will not pass through the separator and thus will remain in the milling chamber. The small size media have a size S2 that is at least smaller than S1 and is preferably smaller than S0. In this invention, large size media optionally in the presence of a fluid carrier are added to the milling chamber. The large size media form a depth filter comprising an array of contacted milling media and voids, channels, and spaces among the milling media particles distributed, stacked or layered on the exit screen of the milling chamber. The small size media are larger than the voids, channels, and spaces of the depth filter and thus will not pass through the depth filter even though they are smaller than the openings in the separator. Subsequently, a conglomerate comprising a solid to be milled, fluid carrier, small size media and optionally additional large size media are added to the milling chamber, and the solid is milled to produce very small particles of solid substrate. The very small particles are smaller than the smallest media size present in the milling chamber. During the milling process, at least a portion of the depth filter proximal to the exit screen is not agitated. The large media particles and the small media particles will not pass through the depth filter and remain in the milling chamber during and after the milling process. The fluid carrier and the very small particles of milled product substrate which are small enough to pass through the spaces, voids, and channels in the depth filter can pass out of the milling chamber and be separated from the milling media. The very fine particles are obtained substantially free of milling media as a dispersion in the fluid carrier.
In another embodiment of the milling process of this invention, large size media of size S1 larger than S0 or a distribution of large size media having an average size S1 in which all are larger than S0 is added to the milling chamber of a media mill. The large size media are allowed to form a depth filter at an exit screen in the milling chamber of the media mill. The depth filter comprises one to several layers of large size media on the exit screen having openings of size S0. An agglomerate comprising a solid substrate to be milled and small size milling media of size S2 smaller than S0 or a distribution of small size media having an average size S2 smaller than S0 or a mixture of said small size media and additional large size media is added to the milling chamber. The solid substrate is mechanically milled by the media to produce very small particles of substrate product. The very small milled product substrate particles are continuously removed from the milling chamber as a dispersion in the fluid carrier and are separated from both the small and the large media by passage through the depth filter together with the fluid carrier. During the milling process, at least one layer of large media of the depth filter remains substantially non-agitated or undisturbed by the movement of any other milling media or substrate particles or fluid carrier in the milling chamber. Essentially none of the large size milling media or the small size milling media are removed from the milling chamber by passing through the openings in the separator. Fluid carrier that passed through the depth filter can be replaced with additional fluid carrier or be recirculated back into the media mill optionally in the form of a fluid carrier dispersion of very small milled substrate particles.
In accordance with this embodiment of the invention, we have discovered a process for preparing a dispersion of solid particles of a milled substrate in a fluid carrier comprising the steps of:
(e) providing a plurality of large size milling media to the milling chamber of a media mill and forming a depth filter therefrom on an exit screen or separator in the milling chamber;
(f) adding to said milling chamber a plurality of small size milling media optionally containing additional large size milling media, a conglomerate of a solid substance comprising a substrate to be milled and optionally one or more than one surface active substance, and a fluid carrier;
(g) milling said conglomerate in said milling chamber to produce very small milled substrate product particles; and
(h) substantially separating said milled substrate particles suspended in said fluid carrier from the media through said depth filter; wherein:
the exit screen comprises openings of size S0;
the large size media have a size distribution S1 of which all are larger than S0;
the small size media have a size distribution S2 which are smaller than S0;
the very small milled substrate particles have a size distribution S3 and are smaller than all of the small media; and
the large size media and the small size media are essentially retained in the milling chamber.
In preferred embodiments of the invention, milling is performed by high speed mixing of the solid conglomerate as a dispersion in the fluid carrier with the media in the milling chamber.
By this process, milling of solid substrate and separation of milled substrate from the milling media are combined in that the media are used for both milling and separation steps. Media separator screen plugging during or after milling is eliminated. Unlike conventional media separation processes, there is minimal loss of dispersion associated with use of a depth filter comprised of large size media. The depth filter and screen may be sized to accomplish both media separation and purification of the dispersion in one step.
While the process in applicable to the wide variety of commercially available media sizes and is useful for milling a wide variety of substrate materials including those heretofore mentioned, it is particularly useful for milling substrates with extremely small media such as media of size less than 350 micrometers which may be effectively separated from milled substrate product particles using this process. Milling media greater than 350 micrometers may be used as small sized media in the presence of larger size media that can form a depth filter on the exit screen of the milling chamber through which the smaller media do not pass.
Depending on the intended use and application, large size milling media can range in size up to the largest size media available for use in a media mill. In one aspect, large size media can be selected from cannon balls, steel shot, ball bearings, and the like. Large size media can have average sizes such as 10 cm, 5 cm, 2 cm, 1 cm, 50 mm, 10 mm, 5 mm, 2 mm, 1 mm, 0.5 mm, and 0.2 mm. Smaller sized milling media can be selected to be smaller than the larger size milling media by a factor of 0.5 times, more preferably by a factor of 0.3 times.
The milling media need not be removed from the milling chamber, thereby minimizing handling of the milled substrate and the media and minimizing chances for contamination.
In a preferred embodiment, a substrate material can be a pharmaceutical compound such as a drug or formulation of a drug useful in treatment of a disease or as a diagnostic agent. The pharmaceutical compound or formulation can be milled in a batch or continuous process using a mixture of small and large particle milling media to obtain sub-micrometer substrate particles dispersed in a fluid carrier.
It is another advantageous feature of this invention that there is provided a milling method which enables the use of ultra-fine milling media, e.g., of a particle size less than 350 micrometers, in a continuous or batch milling process.
It is an advantage that the depth filter restricts the exit of both the larger and smaller size distribution of media during milling but permits the passage of the very small particles of milled substrate, thereby facilitating both grinding of a solid substrate and separation of the very small substrate product particles from both the large and small size distributions of milling media and from residual large particles of substrate that will not pass through the depth filter.
It is a particularly advantageous feature of this invention that there is provided a method of preparing extremely fine particles of pharmaceutical agents, particularly poorly water-soluble or water-insoluble therapeutic and diagnostic agents.
It is another advantageous feature of this invention that there is provided a grinding method which enables the use of ultra-fine grinding media, e.g., of a particle size less than 350 micrometers, in a grinding process.
Other advantageous features will become readily apparent upon reference to the following description of preferred embodiments when in read in light of the accompanying drawings.